Gene Therapy Correction of Aldehyde Dehydrogenase 2 Deficiency

Yuki Matsumura; Katie M Stiles; Jasmine Reid; Esther Z Frenk; Samantha Cronin; Odelya E Pagovich; Ronald G Crystal

doi:10.1016/j.omtm.2019.08.004

Gene Therapy Correction of Aldehyde Dehydrogenase 2 Deficiency

Mol Ther Methods Clin Dev. 2019 Aug 26:15:72-82. doi: 10.1016/j.omtm.2019.08.004. eCollection 2019 Dec 13.

Authors

Yuki Matsumura¹, Katie M Stiles¹, Jasmine Reid¹, Esther Z Frenk¹, Samantha Cronin¹, Odelya E Pagovich¹, Ronald G Crystal¹

Affiliation

¹ Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA.

Abstract

Aldehyde dehydrogenase 2 (ALDH2) deficiency causes "Asian flush syndrome," presenting as alcohol-induced facial flushing, tachycardia, nausea, and headaches. One of the most common hereditary enzyme deficiencies, it affects 35%-40% of East Asians and 8% of the world population. ALDH2 is the key enzyme in ethanol metabolism; with ethanol challenge, the common ALDH2*2 (E487K) mutation results in accumulation of toxic acetaldehyde. ALDH2*2 heterozygotes have increased risk for upper digestive tract cancers, compounded by smoking and drinking alcohol. We hypothesized that a one-time administration of an adeno-associated virus (AAV) gene transfer vector expressing the human ALDH2 coding sequence (AAVrh.10hALDH2) would correct the deficiency state. AAVrh.10hALDH2 was administered intravenously to Aldh2 knockout (Aldh2 ^-/-) and Aldh2 E487K knockin homozygous (Aldh2 ^E487K+/+) mice. Following acute ethanol ingestion, untreated ALDH2-deficient mice had elevated acetaldehyde levels and performed poorly in behavioral tests. In contrast, treated Aldh2 ^-/- and Aldh2 ^E487K+/+ mice had lower serum acetaldehyde levels and improved behavior. Thus, in vivo AAV-mediated ALDH2 therapy may reverse the deficiency state in ALDH2*2 individuals, eliminating the Asian flush syndrome and reducing the risk for associated disorders.

Keywords: AAV; ALDH2; acetaldehyde; gene therapy.